The Chemistry of the Blood-Brain Barrier
- Page ID
- 418899
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\(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)This Exemplar will teach the following concept(s) from the ACS Examinations Institute General Chemistry ACCM
- IX. B. Qualitative observation of matter can be made at a wide range of distance, energy, frequency, and/or time scales
- IX. B. 1. Laboratory observations are made and then often understood in terms of particulate-level models
- IX. B. 3. (a). Rate laws and reaction order are determined using empirical rate data
- VI. H. 2. Gibbs free energy is a state function that simultaneously calculates entropy for the system and surroundings and is useful for determining whether or not a process occurs spontaneously
Introduction:
Our brains are made up of an intricate network of neurons, proteins, and connections that fuel our thinking and information-processing capacity daily. The intersection of the neurological pathways inherent within the brain and chemical principles reveals important layers of understanding how our brains function on a microscopic level. Abbreviated throughout this paper as BBB, the blood-brain barrier is an integral component to ensuring healthy and proper brain power. The BBB is semipermeable: separating the blood from the brain’s extracellular fluid protects the brain from the toxic side effects of drugs and other exogenous molecules.1 In other words, the BBB facilitates the transport of necessary materials into the brain and ensures the blockage of toxins and other harmful substances from the brain’s capillaries that could alter brain activity.
Characteristics of the BBB
Despite being just a single layer of cells, the BBB is composed of multiple cell types; cells themselves are “cemented together” and collaborate to maintain the chemical components of the environment.2 The main cell types include endothelial cells (maintain the permeability of the vessel, regulate passage through the BBB ), pericytes (signal with endothelial cells to influence permeability and growth), astrocytes (support cells that contribute to the structural properties of the BBB), and microglia (immunological defense against potential pathogens or toxins crossing the BBB).3 A unique aspect of the BBB is tight junctions - areas that tie the endothelial cells and are speckled with fewer transport pathways - that control the free movement of molecules and especially prevent water-soluble agents from crossing through cells, including blood leakage into the brain. Figure 1 illustrates these aforementioned cells in the BBB, and Figure 2 shows further components and tight junctions, abbreviated as TJ.
Figure 1. Visualization of the Blood-Brain Barrier3
Additionally, as you can see in Figure 2 below, the cells are depicted as extremely rigid and close together, and while there are methods of transport (mostly vesicular or similar), only one receptor is depicted on the BBB surface in order to emphasize their sparseness. Looking at this image and understanding the difficulty of crossing this tight-knit, defensive force known as the blood-brain barrier, it seems nearly impossible to find or engineer drugs that will cross easily.
Figure 2. Microscopic Visualization of the Blood-Brain Barrier2
Paracellular transport is movement between cells that involves going through tight junctions, while transcellular transport involves movement across the epithelial layer’s cells’ plasma membrane.4 But how exactly does the transport of molecules work?
General Transportation of Molecules Across Membranes
The transportation of molecules is either done through passive or active transport. In active transport, energy is required to move the molecules across the membrane and into the brain and can involve “a protein carrier with a specific binding site that undergoes a change in affinity.”5 Due to the vast number of structures that facilitate active transport across the BBB, we will not be diving further into specific mechanisms, rather classifying active transport as a generalized method of moving molecules that requires input energy.
In passive transport, materials flow along their concentration gradients, thereby consuming no external energy in the process because there is a general thermodynamic tendency to minimize gradients.6 In general, there are three main types of passive transport. Simple diffusion involves molecules randomly moving from high to low concentrations independently without assistance. Facilitated diffusion involves using a transport protein to move solutes from a high to a low concentration with the two main types being channel-mediated diffusion or carrier-mediated diffusion. Another form is simple diffusion through an aqueous channel formed within the membrane.5
Transportation of Molecules in the BBB
There is a multitude of mechanisms for molecules to cross the BBB, both by active and passive transport. Potential examples are demonstrated in Figure 3 below, with A through C being active transport and D through F being passive transport.
Figure 3. Examples of Mechanisms For Cross the BBB7
As paracellular transport is a rare occurrence due to the tight junctions and the mechanisms of active transport are complex, in this paper, we focus on passive transport - particularly the mechanisms of simple and facilitated diffusion.
As mentioned above, these forms of diffusion depend on the concentration of solutes on each side of the blood-brain barrier, and the solute moves from a higher to lower concentration. Thus, the free-energy change (Gibbs-free energy) of a solute diffusing across a membrane is directly dependent on the magnitude of the concentration gradient” (UA). Thus, we are able to derive the equation below5 that relates the change in free energy to the concentration of the different solutes, as used in the example problems below. A more in-depth explanation of the equation can be found here.
\[ ΔG= ΔG^o +(R)(T)ln([C_{inside}]/C_{outside}]) \]
The above equation was found using \( ΔG=ΔG^o +(R)(T)ln(Q) \) where Q is the instantaneous reaction quotient - concentration of products divided by the concentration of reactants.
When \(ΔG_{sys} = 0\) the system is at equilibrium.
When \(ΔG_{sys} < 0\) the reaction is spontaneous.
When \(ΔG_{sys} > 0\) the reaction is nonspontaneous.
In drug development, the logarithmic ratio between the concentration of a compound in the brain and blood is described as the logBB value. This generic value describes the permeability of a molecule across the BBB: high values are often used when stimulating drugs passing the BBB to specific targets in the CNS, and low values indicate lower chances that drugs produce undesirable side effects in the CNS.8
Characteristics of Molecules that Can Cross Via Passive Transport
As passive transport occurs due to concentration gradients without any assistance from transport mechanisms on the BBB, we must investigate the properties of the membrane for transcellular transport. Since the barrier of endothelium cells is largely a lipid bilayer - polar on the outside and nonpolar on the inside - highly lipophilic molecules can cross by simple diffusion.9 Highly lipophilic molecules, in this case, would be lipid soluble, have a low molecular weight (of about 400–600 Daltons), and/or positive charge. Furthermore, there is a correlation between “increased lipid solubility and the rate and extent of penetration into the brain.”10
In case none of the above conditions match, possible mechanisms for molecule movement include carrier-mediated transport, receptor-mediated transport, or absorptive-mediated transport.10 For paracellular transport, these molecules must also be very small and lightweight to cross successfully due to the tight junctions.
Examples of Molecules that Cross the BBB
Blood gases, anesthetics, and opioids are some molecules that enter via passive transport transcellularlly.10 We will be diving into other examples, beginning with a class of drugs that crosses the BBB in this manner: benzodiazepines, which are largely used psychotropic drugs known for their anticonvulsant effects.11
Figure 4. Chlordiazepoxide (Librium), a common benzodiazepine drug12
Above is the structure of Chlordiazepoxide, known as Librium in the pharmaceutical market. While it has a surprising number of dipole moments, the bulky, largely apolar carbon rings counterbalance these polar groups and help the molecule be highly lipophilic, attracted to both the apolar and polar sections of the lipid bilayer. It is also relatively small (only three-ring groups!), which will allow it to pass through the blood-brain barrier much more easily.
Another more common molecule that can easily pass through the BBB is actually alcohol or ethanol.
Figure 5. Ethanol's Structure13
As you can see, ethanol is an incredibly lithe molecule, with a carbon chain and a polar group at one end, making it incredibly lipid soluble and allowing it to pass into the brain easily. While it is commonly used, given its status as an FDA-approved substance, it is important to understand the dangers of consuming alcohol when it can easily access and alter brain chemistry.
As outlined in the introduction, passive transport solely depends on the concentration gradient. Therefore, depending on where the concentration of solutes is higher/lower (inside vs. outside the blood-brain barrier membrane), particles will passively move from one side to the other. Thus, in this scenario, the concentration gradient plays a significant role in mediating which direction the molecules will flow. Similarly, the change in overall free energy is also directly dependent upon the concentration gradient of the particle’s movement, which also ties into the concept of passive transport.
A 21-year-old student at Duke University overindulges at a party on LDOC and consumes an excessive amount of ethanol. Calculate the change in Gibbs Free Energy at 25°C if the concentration of ethanol in the cerebral blood (outside the blood-brain barrier) is 3.2 M and there are 0.10 moles of ethanol in 40.0 mL of solution in the cerebrospinal fluid (the inside of the blood-brain barrier). Based on the calculation for delta G, consider whether ethanol crosses or doesn’t cross the BBB.
Solution
*Note: We assume \(ΔG^o\), the standard free energy change of a reaction, is 0 as the molecules themselves are not chemically changing and no energy would theoretically be released by this reaction.
Step 1: Convert the temperature from Celsius to Kelvin.
\(T = 273 + 25 = 298 K\)
Step 2: Calculate the concentrations of solute, in this case ethanol, outside and inside the BBB.
\([C_o] = 3.2 M \)
\([C_i] = \frac{0.10 mol}{0.040 L} = 2.5 M\)
Step 3: Calculate Q using the concentrations.
\(Q = \frac{2.5 M}{3.2 M} = 0.78125\)
Step 4: Calculate the free energy change of the reaction using Equation 1.
\(ΔG = (\frac{8.3145 J}{mol K})(298K)(\ln(0.78125))\)
\(ΔG = -612 J \)
As \(ΔG < 0\), the reaction is spontaneous and driven towards bringing the solute inside of the BBB, so ethanol does cross the BBB.
Difficulties in Crossing the BBB
However, not all drugs are able to sneak through the BBB. For instance, highly reactive groups, including H bond donors9, and large sizes, weight, and complexity of molecules will also inhibit the success of drugs crossing the BBB, essentially forcing scientists to engineer a way to get their drugs through the barrier. There are numerous invasive and noninvasive techniques. Notable invasive techniques include intracerebroventricular fusion - injecting drugs directly into the cerebrospinal fluid and transient disruption - shrinking endothelial cells to break down tight junctions. Noninvasive techniques include modifying drugs with lipid and functional groups so they can cross the membrane directly or using transport/carrier systems, inhibiting efflux transporters, nanoparticle-based technology, gene therapy, and “molecular trojan horse delivery systems” in which a drug that cannot cross the BBB is coupled to a peptide protein that can cross, allowing the drug to utilize receptor-mediated transport.14 An example of this engineering process is ℒ-DOPA. A precursor to dopamine and treatment for Parkinson’s disease, L-DOPA is a large neutral amino acid that is transported across the BBB via the LAT1 neutral amino-acid carrier, a carrier-mediated transporter.14
We will investigate if dopamine itself can cross the BBB. It is often intravenously administered (IV drip) to treat low blood pressure, low heart rate, and cardiac arrest as it is a peripheral vasostimulant, essentially opening up the arteries.15
Calculate the change in Gibbs Free Energy at 30°C if the concentration of dopamine in the cerebral blood (outside the blood-brain barrier) is 2.7 M and there are 0.1 moles of dopamine in 30.0 mL of solution in the cerebrospinal fluid (inside of the blood-brain barrier). Based on the calculation for ΔG, consider whether dopamine crosses or doesn’t cross the BBB.
Solution
*Note: We assume \(ΔG^o\), the standard free energy change of a reaction, is 0 as the molecules themselves are not chemically changing and no energy would theoretically be released by this reaction. Step 1: Convert the temperature from Celsius to Kelvin.
\(T = 273 + 30 = 303 K\)
Step 2: Calculate the concentrations of solute, in this case ethanol, outside and inside the BBB.
\([C_o] = 2.7 M \)
\([C_i] = \frac{0.10 mol}{0.030 L} = 3.33 M\)
Step 3: Calculate Q using the concentrations.
\(Q = \frac{3.33 M}{2.7 M} = 1.233\)
Step 4: Calculate the free energy change of the reaction using Equation 1.
\(ΔG = (\frac{8.3145 J}{mol K})(303K)(\ln(1.233))\)
\(ΔG = +528 J \)
As \(ΔG > 0\), the reaction is nonspontaneous and driven towards bringing the solute outside of the BBB, so dopamine does not cross the BBB unless there is a coupled reaction or another mechanism.
References
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12. National Library of Medicine. Chlordiazepoxide. https://pubchem.ncbi.nlm.nih.gov/com...lordiazepoxide (accessed November 10, 2022).
13. National Library of Medicine. Ethanol. https://pubchem.ncbi.nlm.nih.gov/com...n=2D-Structure (accessed November 10, 2022).
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15. James Sonne; Amandeep Goyal; Wilfredo Lopez-Ojeda. Dopamine. In StatPearls [Online] StatPearls Publishing: Treasure Island, FL, 2022. National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK535451/ (accessed November 10, 2022)